HALOGENATED BIOGENIC AMINES IN BIOCHEMISTRY AND PHARMACOLOGY

生物化学和药理学中的卤化生物胺

• 批准号: 5201965
• 负责人: K L KIRK
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5201965
• 关键词: adrenergic receptor; alpha adrenergic agent; beta adrenergic agent; chemical structure function; chemical substitution; chemical synthesis; conformation; dopamine; dopamine receptor; epinephrine; fluorine; halogenation; neuropharmacology; neurotransmitter metabolism; neurotransmitters; norepinephrine; prodrugs

Biogenic amines play key roles in neurotransmission, metabolism, and in control of various physiological processes. Using a variety of synthetic methodologies, including novel procedures developed by us, we have prepared a series of biogenic amines with flourine substituted at various ring-positions. By virtue of its very small size and high electronegativity, flourine is a very favorable replacement for hydrogen in these analogues. The biological properties and usefulness of these ring-fluorinated biogenic amines have proved to be extremely rewarding and continue to find applications in a multitude of studies, including research on the mechanisms of transport, storage, release, metabolism, and modes of action of these amines. Of particular significance was the discovery that 6-flouronorepinephrine is a selective alpha-adrenergic agonist and 2-fluoronorepinephrine is a selective beta-adrenergic agonist. Mechanisms considered to explain these results include; 1) a direct effect of the C-F bond on agonist-receptor interaction or 2) an indirect effect of the C-F bond on the conformation of the ethanolamine side-chain. The results of testing of new analogues synthesized to probe these mechanisms have not clearly differentiated between these two basic mechanisms. Binding of fluorinated analogues to cloned wild-type and mutant adrenergic receptors has been carried out in an attempt to identify specific sites on the receptor protein responsible for fluorine-induced adrenergic selectivities. We have developed stereoselective syntheses of threo-2-and 6- fluorodihydroxyphenylserine (fluoro-DOPS). A new synthesis of fluorinated and polyfluorinated veratraldehydes, based on direct electrophilic fluorination, has been realized, and we have prepared all mono- and difluorinated analogues of veratraldehyde as well as trifluorovertraldehyde. These are being used to prepare the corresponding biogenic amines and their amino acid precursors. Examination of the interactions of the mono-, di-, and trifluoroanalogues of dopamine with D-1, D-2, and D-3 dopamine receptors has been carried out. Aminocyclopropane carboxylic acid (ACCA) has been shown by others to provide protection from damage due to stroke of central neurons.

生物胺在神经传递、新陈代谢和 各种生理过程的控制。 采用多种合成 方法论，包括我们开发的新颖程序，我们有 制备了一系列氟取代的生物胺 环位置。 凭借其非常小的尺寸和高 电负性，氟是氢的非常有利的替代品 在这些类似物中。 这些物质的生物学特性和用途 环氟化生物胺已被证明是非常有价值的 并继续在众多研究中寻找应用，包括 运输、储存、释放、代谢机制研究， 以及这些胺的作用方式。 特别重要的是 发现 6-氟肾上腺素是一种选择性 α-肾上腺素能药物 激动剂和2-氟去甲肾上腺素是一种选择性β-肾上腺素能药物 激动剂。 考虑解释这些结果的机制包括： 1） C-F 键对激动剂-受体相互作用的直接影响或 2) C-F键对构象的间接影响 乙醇胺侧链。 新类似物的测试结果 合成来探索这些机制尚未明确区分 这两个基本机制之间。 氟化类似物与 已克隆野生型和突变型肾上腺素受体 试图识别受体蛋白上的特定位点 负责氟诱导的肾上腺素能选择性。 我们有 开发了 threo-2- 和 6- 的立体选择性合成 氟二羟基苯基丝氨酸（氟-DOPS）。 一个新的合成 氟化和多氟化藜芦醛，基于直接 亲电氟化，已经实现，我们已经准备好了 藜芦醛的单氟化和二氟化类似物以及 三氟戊醛。 这些正在被用来准备 相应的生物胺及其氨基酸前体。 检查单氟、二氟和三氟类似物的相互作用 多巴胺与 D-1、D-2 和 D-3 多巴胺受体已被携带 出去。 氨基环丙烷甲酸 (ACCA) 已被其他人证明 提供保护，免受中枢神经元中风造成的损伤。